page_title: WNK4
section_title: Function
hierarchical_section_title: WNK4 / Function
caption_attribution_description: English: WNK4-SPAK-NCC
context_page_description: Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome.
  WNK4 is a member of a serine/threonine kinase family that comprises of four members. The family is so named because unlike other serine/threonine kinases, WNKs are characterized by the lack of the lysine in the subdomain II of the catalytic domain. Instead, a lysine in the β2 strand of subdomain I of the catalytic domain is responsible for the kinase activity.
  The WNK4 gene is located on chromosome 17q21-q22. It produces a 1,243-amino acid protein encoded by a 3,732-nucleotide open reading frame within a 4 kb cDNA transcript. WNK4 protein is highly expressed in the distal convoluted tubule and the cortical collecting duct of the kidney. WNK4 is also present in the brain, lungs, liver, heart, and colon of various mammalian species.
  Gene mutations in WNK4 has been found in patients with pseudohypoaldosteronism type II, also known as familial hyperkalemic hypertension or Gordon syndrome.
context_section_description: As a typical kinase, WNK4 accomplishes the phosphorylation of its substrate proteins by adding a phosphate moiety in an ATP-dependent manner. This structural modification usually results in functional alterations of downstream substrates. Some currently known substrates of WNK4 includes kinases STE20-serine-proline alanine-rich kinase (SPAK) and oxidative stress response 1 kinase (OSR1), which in turn can phosphorylate and activate the thiazide-sensitive sodium-chloride cotransporter (NCC) (Fig. 2). Similarly, WNK4 activates NKCC1 and deactivate KCC2 through a SPAK-dependent mechanism. The kinase activity of WNK4 has been demonstrated in vitro using the WNK4 kinase domain purified from E. coli. This phosphorylation cascade is critical in regulating sodium and potassium homeostasis dysregulation which is tied to the pathogenesis of PHAII.
  In addition to NCC, WNK4 also regulates multiple ions channels and cotransporters in the kidney through various mechanisms. These include epithelial Na⁺ channel (ENaC), renal outer medullary potassium channel (ROMK), transient receptor potential vanilloid member 4 and 5 (TRPV4/5, calcium channels), Na-K-2Cl cotransporter 1 and 2 (NKCC1/2), K⁺-Cl⁻ cotransporter type 2 (KCC2), and other channels/transporters. WNK4 inhibits the functions of ENaC, ROMK, and TRPV4 by reducing the total and cell surface expression of these channels. WNK4 enhances TRPV5 by increasing its forward trafficking to the plasma membrane in a kinase-dependent manner. The inhibitory effect of WNK4 on ROMK is reversed by serum and glucocorticoid kinase 1 (SGK1) or by a corresponding phosphomimetic S1169D mutation on WNK4. The N-terminal segment of WNK4 containing the kinase domain and acidic motif is required for the WNK4-mediated inhibition of ROMK. The second coiled-coil domain of WNK4 mediates the downregulation of TRPV4. WNK4 and calcium-binding protein 39 (Cab39) act together to activate transporters NKCC1 and NKCC2.
caption: Fig. 2. The WNK4-SPAK/OSR1-NCC phosphorylation cascade. WNK4 phosphorylates and activates SPAK/OSR1, which in turn phosphorylate and activates NCC. In this manner, WNK4 regulates sodium reabsorption in the distal convoluted tubule and downstream potassium secretion through its positive effects on NCC.
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